2. Academic Validation
  3. METTL4 regulates synaptic UCP2 N6-adenosine methylation to mediate pain hypersensitivity in female mice

METTL4 regulates synaptic UCP2 N6-adenosine methylation to mediate pain hypersensitivity in female mice

  • Cell Mol Life Sci. 2025 Dec 27;83(1):44. doi: 10.1007/s00018-025-06010-2.
Yanqiong Wu 1,  Yifan Luo 2,  Qin Xiao 2,  Xueqin Xu 2,  Wenjiao Jin 2,  Longhui Li 2,  Cheng Liu 1,  Zhigang He 1,  Zhixiao Li 1,  Juan Li 1,  Xuesong Yang 1,  Fan Jiang 1,  Zeyong Yang 3,  Daqing Ma 4 5,  Changbin Ke 6,  Hongbing Xiang 7
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, China.
  • 2 Institute of Anesthesiology & Pain, Departments of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
  • 3 Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200030, China.
  • 4 Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
  • 5 Perioperative and Systems Medicine, Department of Anesthesiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
  • 6 Institute of Anesthesiology & Pain, Departments of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China. [email protected].
  • 7 Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, China. [email protected].
PMID: 41454926 DOI: 10.1007/s00018-025-06010-2
Abstract

Epitranscriptomics modifications play an important role in sex-dependent biological phenomena. N6-adenosine methylation (m6A), the most prevalent epitranscriptomics modification in eukaryotic mRNA, participates in regulating various sex-specific physiological processes. Here, we generated METTL4 knockout mice lacking methyltransferase-like 4, which mediates m6A. Behavioral analyses revealed that only female METTL4-/- mice exhibited pain hypersensitivity, with subsequent experiments showing the involvement of METTL4-mediated m6A in this sex-differentiated biological phenotype. Further exploration demonstrated that this sex-specific pain hypersensitivity is closely associated with sex-dependent expression of uncoupling protein 2 (UCP2) in synapses. Specifically, elevated UCP2 expression in METTL4-/- female mice enhances the efficiency of synaptic transmission by modulating mitochondrial energy metabolism at synapses. Collectively, this study identifies a distinct pathway mediated by METTL4-driven m6A modification, providing critical insights into the molecular basis of sex-specific differences in pain transmission. These findings also highlight the potential of targeting METTL4 for sex-differentiated pain management strategies in clinical settings.

Keywords

M6A; METTL4; Mitochondrial metabolism; Pain hypersensitivity; Sexual dimorphism; Synaptic transmission; UCP2.

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